title: Lithium chloride attenuates cell death in oculopharyngeal muscular dystrophy by perturbing Wnt/β-catenin pathway.
abstract: Expansion of polyalanine tracts causes at least nine inherited human diseases. Among these, a polyalanine tract expansion in the poly (A)-binding protein nuclear 1 (expPABPN1) causes oculopharyngeal muscular dystrophy (OPMD). So far, there is no treatment for OPMD patients. Developing drugs that efficiently sustain muscle protection by activating key cell survival mechanisms is a major challenge in OPMD research. Proteins that belong to the Wnt family are known for their role in both human development and adult tissue homeostasis. A hallmark of the Wnt signaling pathway is the increased expression of its central effector, beta-catenin (β-catenin) by inhibiting one of its upstream effector, glycogen synthase kinase (GSK)3β. Here, we explored a pharmacological manipulation of a Wnt signaling pathway using lithium chloride (LiCl), a GSK-3β inhibitor, and observed the enhanced expression of β-catenin protein as well as the decreased cell death normally observed in an OPMD cell model of murine myoblast (C2C12) expressing the expanded and pathogenic form of the expPABPN1. Furthermore, this effect was also observed in primary cultures of mouse myoblasts expressing expPABPN1. A similar effect on β-catenin was also observed when lymphoblastoid cells lines (LCLs) derived from OPMD patients were treated with LiCl. We believe manipulation of the Wnt/β-catenin signaling pathway may represent an effective route for the development of future therapy for patients with OPMD.
authors.affiliation: The Montreal Neurological Institute and Hospital, Department of Medicine, McGill University, Montréal, Québec H3A2B4, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Abu-Baker
authors.forename: J
authors.initials: J
authors.lastname: Laganiere
authors.forename: R
authors.initials: R
authors.lastname: Gaudet
authors.forename: D
authors.initials: D
authors.lastname: Rochefort
authors.forename: B
authors.initials: B
authors.lastname: Brais
authors.forename: C
authors.initials: C
authors.lastname: Neri
authors.forename: P A
authors.initials: PA
authors.lastname: Dion
authors.forename: G A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology* / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D039141:Muscular Dystrophy, Oculopharyngeal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D050505:Mutant Proteins / Q000378:metabolism; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D039122:Poly(A)-Binding Protein I / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D039122:Poly(A)-Binding Protein I; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D018021:Lithium Chloride